The sialic acids are a diverse family of α-keto sugars, sharing a defining 9-carbon structural skeleton, and are typically the outermost moiety of oligosaccharides on vertebrate glycolipids and glycoproteins. They are generally attached to the underlying sugar chain via an α-glycosidic linkage between their 2-position (FIG. 1) and either the 3- or 6-hydroxyl group of galactose or N-acetylgalactosamine, the 6-hydroxyl group of N-acetylglucosamine, or they may also exist as α2,8-linked homopolymers (Lehman et al., 2006). With the presence of various substitutions at their 4, 5, 7, 8 and 9 positions (Varki and Varki, 2007), their various linkages, as well as their prominent and accessible location, it is not surprising this diverse family of sugars mediates and/or modulates a multitude of cellular interactions. Intercellular adhesion and signaling often results from sialic acid-specific binding proteins, or lectins, present on mammalian cell surfaces, most noted for their importance in regulating the immune system and in neuronal development. For example, the Siglecs (Sia-recognizing lg-superfamily lectins) MAG and CD22 are involved in the binding of glial cells to gangliosides, which is critical to the long-term stability of myelin as well as inhibition of neurite outgrowth, and in negatively regulating B-cell function, respectively (Varki and Angata, 2006; Crocker et al., 2007; Varki, 2007). In addition, the neural cell adhesion molecule (NCAM) possesses α2,8-linked poly-sialic acid, which is important for brain development and neural regeneration, while its expression correlates with poor prognosis for several neuroendocrine tumours (Bork et al., 2007). Another example of sialic acid having prognostic significance in human cancer is the enhanced expression of α2,6-linked sialic acid on N-glycans, correlating with cancer progression, metastatic spread and poor prognosis for colon, breast and cervical cancers, to name a few (Hedlund et al., 2008).
It is possible that the importance of sialic acids within humans has contributed to the abundance of pathogens that display, bind or catabolize sialic acid. In fact, sialic acids are now recognized as the receptor or ligand most frequently used by pathogenic viruses, bacteria, and protozoa (Lehman et al., 2006). Furthermore, pathogenic bacteria have gained the ability to display sialic acids on their surface, either by de novo synthesis or through specific scavenging mechanisms, which is believed to influence pathogenesis through immune evasion, adhesion and invasion (Hsu et al., 2006; Severi et al., 2007). For example, the poly-sialic acid capsules of Neisseria meningitidis B and Escherichia coli K1 are poorly immunogenic, likely due to their molecular mimicry with the poly-sialic acid found on NCAM. In addition to utilizing host sialic acids as nutrient sources, many pathogenic bacteria possess sialic acid-specific lectins, which assist host-pathogen interactions and ultimately pathogenesis. Interestingly, they may also deploy soluble lectins, or toxins, that bind sialoglycoconjugates, such as the AB5 cholera toxin that recognizes the GM1 ganglioside (Angstrom et al., 1994; Merrit et al., 1998), and pertussis toxin that recognizes the GD1a ganglioside (Hausman and Burns, 1993; Stein et al., 1994). Finally, an increasing number of protozoal pathogens have been found to utilize sialic acid-specific lectins, such as Plasmodium spp., the causative agent of malaria (Lehman et al., 2006). Moreover, Trypanosomes possess a cell-surface trans-sialidase allowing these organisms to coat themselves with mammalian derived sialic acid (Pontes de Carvalho et al., 1993).
In addition to presenting sialic acids on their surface, bacteria can also incorporate sialic acid-like sugars (5,7-diacetamido-3,5,7,9-tetradeoxy-nonulosonate derivatives) into their virulence-associated cell-surface glycoconjugates, such as lipopolysaccharide (LPS), capsular polysaccharide, pili and flagella (Schoenhofen et al., 2006b). These sugars (FIG. 1) are unique to microorganisms and may exhibit configurational differences compared with sialic acid. One particular sialic acid-like sugar, legionaminic acid (5,7-diacetamido-3,5,7,9-tetradeoxy-D-glycero-D-galacto-nonulosonic acid; X), has the same absolute configuration as sialic acid. Legionaminic acid was first identified in 1994 to be a component of Legionella pneumophila serogroup 1 LPS, hence its name (Knirel at al., 1994). However, it wasn't until 2001 that its correct stereochemistry was realized using synthetic methods (Tsvetkov et al., 2001). L. pneumophila, the causative agent of Legionnaires' disease, invades and replicates within alveolar macrophages leading to a debilitating and sometimes fatal pneumonia (Kooistra et al., 2002). The role of legionaminic acid in this disease progression may be significant, as it has been suggested that LPS is a key determinant in the ability of L. pneumophila to inhibit the fusion of phagosomes with lysosomes (Fernandez-Moreira et al., 2006). L. pneumophila serogroup 1 LPS contains both legionaminic acid and its 4-epimer isomer 4-epi-legionaminic acid (FIG. 1), although the majority appears to be an α2,4-linked homopolymer of legionaminic acid (Knirel et al., 2003). Interestingly, the first report of a proteoglycan containing legionaminic acid (X) was the recent discovery of this sugar on the flagellins of the gastrointestinal pathogen Campylobacter coil (McNally et al., 2007). Here, a number of Campylobacter genes were identified as being critical to its synthesis by screening isogenic mutants for the presence of CMP-legionaminic acid (XI) metabolites.